Dendrimer chemistry is expanding at a rapid rate. Dendrimers are being adapted for pharmacological uses, industrial uses, coatings, as well as other areas where unimolecular isolar molecules can be engineered to provide specific chemical properties to a system. For example, dendrimers can be used as carriers of drugs, metals, or the like and site directed to specific low side. Dendrimers can also be used in or as coatings to, for example, impart a homogeneous layer to a substrate.
In producing dendritic macromolecules, especially those which are megatiered (four tiers and greater), there is a continued inability to determine quantitatively or qualitatively the absolute homogeneity of the resultant structures. This has lead many researchers to claim a monodisperse character of their products, since there is no way to insure monomolecular structure.
By monodisperse, it is meant that the dendrimer is defined as a mixture of closely related macromolecules within a given family. These molecules include what are considered “faults”, albeit they may be to only a minimum degree.1 A monomolecular dendrimer means herein that a perfectly defined structure of known composition, possessing no detectable faults is obtained.
In the efforts to determine the existence of faults in dendritic molecular domains, there has been an inability to effect chromatographic separation of the macromolecular components. This has been coupled with the general lack of resolution of spectral analysis associated with current instrumentation. This situation has lead researchers to a quest for chemical methods to circumvent this quandry.
It has been recognized in accordance with the present invention that most divergent procedures for obtaining dendritic macromolecules are two step coupling-deprotecting sequences. It has therefore been recognized, in accordance with the present invention, that it is feasible to analyze those uncoupled termini, the uncoupled termini being referred to as “loose ends”. These uncoupled termini are effectively loose ends in that they represent the heterogeneity of the otherwise homogeneous molecule. The loose ends represent heterogeneity in that they are reactive components or at least capable of reactivity which is differentially effected relative to the remainder of the macromolecule. In other words, the present invention recognizes the uncoupled termini as areas of reactivity which can be differentiated from the remainder of the macromolecule.
Illustrative of the above chemically defined situation wherein dendritic molecules have uncoupled termini, FIG. 1 shows the introduction of faults during the creation2 of a dendritic polyamido-based dendritic family. This family is chemically described as Z-Cascade:methane[4]:(3-oxo-6-oxa-2-azahaptylidene):(3-oxo-2-azapent-ylidyne)n:propanoic acid.3 Practically, this series of dendritic molecules is formed by a repetitive treatment of a polycarboxylic acid with “Behera's Amine”4 by a peptide coupling procedure5, followed by quantitative hydrolysis with formic acid to afford higher generations. The purity or monodispersed character of each resultant macromolecule was monitored by normal spectroscopic and analytical procedures. A problem was reached beyond the third generation of the macromolecule. The analytical procedures normally used in the prior art were less definitive as to the monodispersity and, in particular, “unimolecular” character of the larger products. This general observation is consistent with all current divergent procedures used for generating dendritic macromolecules.
In order to circumvent the above limitations relating to the inability of confirming unimolecular character of larger products, the inventors of the present invention reported the creation of bis-dendrimers6. These bis-dendrimers were assembled by the coupling of two totally characterized halves through a metal ion connectivity. The presence of the metal's content and oxidation state was then ascertained electro-chemically.
The present invention provides a novel application of traditional qualitative analysis procedures7 to evaluate the presence of residual termini which fail to react during a coupling procedure. Hence, the present invention provides a method of detecting unreacted termini within a dendritic structure. Likewise, the present invention provides a method of characterizing the termini of dendrimers as well as determining the monodisperse versus monomolecular character of a dendrimer. Such methods find utility in characterizing dendrimers made by diverse methods as the characterization procedure is not dependent upon the method by which the dendrimers were constructed. Rather, the inventor procedure can be utilized for the characterization of dendrimers made by any procedure which is divergent in character.